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Molecular Determinants of Cardiac Arrhythmias
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Molecular Determinants of Cardiac Arrhythmias

A special issue of Hearts (ISSN 2673-3846).

Deadline for manuscript submissions: closed (28 February 2021) | Viewed by 17610

Special Issue Editor

Prof. Dr. Diego Franco Jaime

E-Mail Website
Guest Editor
Departamento de Biología Experimental, Universidad de Jaen, 23071 Jaen, Spain
Interests: cardiovascular development; transcriptional regulation; noncoding RNAs; atrial fibrillation
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Cardiac arrhythmias constitute one of the major burdens in medical practice. Atrial fibrillation is the most frequent arrhythmia, with an estimated prevalance of 2–4% in the general population increasing to >10% in the elderly. Sudden cardiac death (SCD), mostly due to ventricular fibrillation, represents a major worldwide public health problem, accounting for 15–20 % of all deaths. Other arrhythmias such as Brugada, long-QT, and short-QT, although having a lower prevalence, similarly provide enormous concerns in terms of societal distress, public health, and medical treatment. Over the last decades, our understanding of the cellular, molecular, and genetics bases of arrhythmogenesis has exponentially increased, including the identification of genetic hallmarks and the identification of electrophysiological and electromechanical bases. Recently, novel insights have been gained via the identification of novel regulatory mechanisms contributing to the onset and course of cardiac arrhythmias, including diverse epigenetic mechanisms. In this Special Issue, we aim to gather state-of-the-art insights into the cellular, molecular, genetic, and epigenetic mechanisms involved in cardiac arrhythmias.

Prof. Dr. Diego Franco Jaime
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Hearts is an international peer-reviewed open access quarterly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • arrhythmias
  • atrial fibrillation
  • ventricular fibrillation
  • longQT syndrome
  • Brugada syndrome
  • ion channels
  • microRNAs
  • lncRNAs
  • transcriptional regulation

Published Papers (5 papers)

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Editorial

Jump to: Research, Review

3 pages, 173 KiB  
Editorial
Molecular Determinants of Cardiac Arrhythmias
by Diego Franco
Hearts 2020, 1(3), 146-148; https://doi.org/10.3390/hearts1030014 - 30 Oct 2020
Cited by 1 | Viewed by 1776
Abstract
Cardiac arrhythmias are defined as electrical disorders of the pumping heart, including therein a wide range of physiopathological entities [...] Full article
(This article belongs to the Special Issue Molecular Determinants of Cardiac Arrhythmias)

Research

Jump to: Editorial, Review

19 pages, 22799 KiB  
Article
Novel PITX2 Homeodomain-Contained Mutations from ATRIAL Fibrillation Patients Deteriorate Calcium Homeostasis
by Adela Herraiz-Martínez, Carmen Tarifa, Estefanía Lozano-Velasco, Verónica Jiménez-Sábado, Sergi Casabella, Francisco Hernández-Torres, Houria Daimi, Eduardo Vázquez Ruiz de Castroviejo, Eva Delpón, Ricardo Caballero, Amelia Aránega, Diego Franco and Leif Hove-Madsen
Hearts 2021, 2(2), 251-269; https://doi.org/10.3390/hearts2020020 - 05 May 2021
Cited by 4 | Viewed by 2622
Abstract
Atrial fibrillation (AF) is the most common cardiac arrhythmia in the human population, with an estimated incidence of 1–2% in young adults but increasing to more than 10% in 80+ years patients. Pituitary Homeobox 2, Paired Like Homeodomain 2 (PITX2c) loss-of-function in mice [...] Read more.
Atrial fibrillation (AF) is the most common cardiac arrhythmia in the human population, with an estimated incidence of 1–2% in young adults but increasing to more than 10% in 80+ years patients. Pituitary Homeobox 2, Paired Like Homeodomain 2 (PITX2c) loss-of-function in mice revealed that this homeodomain (HD)-containing transcription factor plays a pivotal role in atrial electrophysiology and calcium homeostasis and point to PITX2 as a candidate gene for AF. To address this issue, we recruited 31 AF patients for genetic analyses of both the known risk alleles and PITX2c open reading frame (ORF) re-sequencing. We found two-point mutations in the homedomain of PITX2 and three other variants in the 5’untranslated region. A 65 years old male patient without 4q25 risk variants but with recurrent AF displayed two distinct HD-mutations, NM_000325.5:c.309G>C (Gln103His) and NM_000325.5:c.370G>A (Glu124Lys), which both resulted in a change within a highly conserved amino acid position. To address the functional impact of the PITX2 HD mutations, we generated plasmid constructs with mutated version of each nucleotide variant (MD4 and MD5, respectively) as well as a dominant negative control construct in which the PITX2 HD was lacking (DN). Functional analyses demonstrated PITX2c MD4 and PITX2c MD5 decreased Nppa-luciferase transactivation by 50% and 40%, respectively, similar to the PITX2c DN (50%), while Shox2 promoter repression was also impaired. Co-transactivation with other cardiac-enriched co-factors, such as Gata4 and Nkx2.5, was similarly impaired, further supporting the pivotal role of these mutations for correct PITX2c function. Furthermore, when expressed in HL1 cardiomyocyte cultures, the PITX2 mutants impaired endogenous expression of calcium regulatory proteins and induced alterations in sarcoplasmic reticulum (SR) calcium accumulation. This favored alternating and irregular calcium transient amplitudes, causing deterioration of the beat-to-beat stability upon elevation of the stimulation frequency. Overall this data demonstrate that these novel PITX2c HD-mutations might be causative of atrial fibrillation in the carrier. Full article
(This article belongs to the Special Issue Molecular Determinants of Cardiac Arrhythmias)
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Review

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24 pages, 1178 KiB  
Review
Non-Coding RNAs in the Cardiac Action Potential and Their Impact on Arrhythmogenic Cardiac Diseases
by Estefania Lozano-Velasco, Amelia Aranega and Diego Franco
Hearts 2021, 2(3), 307-330; https://doi.org/10.3390/hearts2030026 - 30 Jun 2021
Cited by 2 | Viewed by 4296
Abstract
Cardiac arrhythmias are prevalent among humans across all age ranges, affecting millions of people worldwide. While cardiac arrhythmias vary widely in their clinical presentation, they possess shared complex electrophysiologic properties at cellular level that have not been fully studied. Over the last decade, [...] Read more.
Cardiac arrhythmias are prevalent among humans across all age ranges, affecting millions of people worldwide. While cardiac arrhythmias vary widely in their clinical presentation, they possess shared complex electrophysiologic properties at cellular level that have not been fully studied. Over the last decade, our current understanding of the functional roles of non-coding RNAs have progressively increased. microRNAs represent the most studied type of small ncRNAs and it has been demonstrated that miRNAs play essential roles in multiple biological contexts, including normal development and diseases. In this review, we provide a comprehensive analysis of the functional contribution of non-coding RNAs, primarily microRNAs, to the normal configuration of the cardiac action potential, as well as their association to distinct types of arrhythmogenic cardiac diseases. Full article
(This article belongs to the Special Issue Molecular Determinants of Cardiac Arrhythmias)
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18 pages, 4917 KiB  
Review
Molecular Basis of Atrial Fibrillation Initiation and Maintenance
by Kira Beneke and Cristina E. Molina
Hearts 2021, 2(1), 170-187; https://doi.org/10.3390/hearts2010014 - 23 Mar 2021
Cited by 4 | Viewed by 3872
Abstract
Atrial fibrillation (AF) is the most common cardiac arrhythmia, largely associated to morbidity and mortality. Over the past decades, research in appearance and progression of this arrhythmia have turned into significant advances in its management. However, the incidence of AF continues to increase [...] Read more.
Atrial fibrillation (AF) is the most common cardiac arrhythmia, largely associated to morbidity and mortality. Over the past decades, research in appearance and progression of this arrhythmia have turned into significant advances in its management. However, the incidence of AF continues to increase with the aging of the population and many important fundamental and translational underlaying mechanisms remain elusive. Here, we review recent advances in molecular and cellular basis for AF initiation, maintenance and progression. We first provide an overview of the basic molecular and electrophysiological mechanisms that lead and characterize AF. Next, we discuss the upstream regulatory factors conducting the underlying mechanisms which drive electrical and structural AF-associated remodeling, including genetic factors (risk variants associated to AF as transcriptional regulators and genetic changes associated to AF), neurohormonal regulation (i.e., cAMP) and oxidative stress imbalance (cGMP and mitochondrial dysfunction). Finally, we discuss the potential therapeutic implications of those findings, the knowledge gaps and consider future approaches to improve clinical management. Full article
(This article belongs to the Special Issue Molecular Determinants of Cardiac Arrhythmias)
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19 pages, 1287 KiB  
Review
Optical Mapping in hiPSC-CM and Zebrafish to Resolve Cardiac Arrhythmias
by Bert Vandendriessche, Ewa Sieliwonczyk, Maaike Alaerts, Bart L. Loeys, Dirk Snyders and Dorien Schepers
Hearts 2020, 1(3), 181-199; https://doi.org/10.3390/hearts1030018 - 21 Dec 2020
Cited by 2 | Viewed by 4094
Abstract
Inherited cardiac arrhythmias contribute substantially to sudden cardiac death in the young. The underlying pathophysiology remains incompletely understood because of the lack of representative study models and the labour-intensive nature of electrophysiological patch clamp experiments. Whereas patch clamp is still considered the gold [...] Read more.
Inherited cardiac arrhythmias contribute substantially to sudden cardiac death in the young. The underlying pathophysiology remains incompletely understood because of the lack of representative study models and the labour-intensive nature of electrophysiological patch clamp experiments. Whereas patch clamp is still considered the gold standard for investigating electrical properties in a cell, optical mapping of voltage and calcium transients has paved the way for high-throughput studies. Moreover, the development of human-induced pluripotent stem-cell-derived cardiomyocytes (hiPSC-CMs) has enabled the study of patient specific cell lines capturing the full genomic background. Nevertheless, hiPSC-CMs do not fully address the complex interactions between various cell types in the heart. Studies using in vivo models, are therefore necessary. Given the analogies between the human and zebrafish cardiovascular system, zebrafish has emerged as a cost-efficient model for arrhythmogenic diseases. In this review, we describe how hiPSC-CM and zebrafish are employed as models to study primary electrical disorders. We provide an overview of the contemporary electrophysiological phenotyping tools and discuss in more depth the different strategies available for optical mapping. We consider the current advantages and disadvantages of both hiPSC-CM and zebrafish as a model and optical mapping as phenotyping tool and propose strategies for further improvement. Overall, the combination of experimental readouts at cellular (hiPSC-CM) and whole organ (zebrafish) level can raise our understanding of the complexity of inherited cardiac arrhythmia disorders to the next level. Full article
(This article belongs to the Special Issue Molecular Determinants of Cardiac Arrhythmias)
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